10例脑外伤病人硫酸妥布霉素的药物动力学特性

目的：比较硫酸妥布霉素ｉｖ ｇｔｔ或气管滴入的药物动力学。方法：用ＦＰＩＡ法测定１０例脑外伤病人ｉｖ ｇｔｔ或气管滴入硫酸妥布霉素后的血药浓度。结果：２种给药方法均符合一房室模型的药物动力学特征，且给药后２ｈ均能达到有效血浓度（２￣１２μｇ／ｍｌ），但血药浓度及主要药物动力学参数个体差异较大。结论：ｉｖ ｇｔｔ给药和于脑外伤短期预防给药、气管滴入能有效地预防肺部感染。     

静脉注射乌苯美司/5-氟尿嘧啶在大鼠体内的药动学研究

目的:建立大鼠静脉注射乌苯美司/5-氟尿嘧啶(Bes/5-FU)后血药浓度的检测方法,并研究其药动学特征。方法:取6只大鼠股静脉注射Bes/5-FU生理氯化钠溶液84 mg/kg,给药后0.033、0.083、0.167、0.333、0.5、1、2、3、4、6、8、10 h经眼底静脉丛取血,高效液相色谱法分别检测Bes/5-FU和5-FU的血药浓度,用DAS 2.0分析软件计算给药后代谢产物5-FU的药动学参数。色谱柱为Venusil ASB C18,流动相为乙腈-0.05%甲酸(22∶78)(Bes/5-FU)、甲醇-水(5∶95)(5-FU),流速为1 ml/min,检测波长为262.7 nm(Bes/5-FU)、266 nm(5-FU),柱温为25℃,进样量为30μl(Bes/5-FU)、20μl(5-FU)。结果:Bes/5-FU给药后2 h在大鼠体内已基本代谢完全。5-FU药动学参数t1/2为(0.14±0.04)h,MRT0-10 h为(0.17±0.04)h,AUC0-10 h为(17.73±6.27)μg·h/ml,AUC0-∞为(17.78±6.31)μg·h/ml。结论:本方法可快速、准确地检测Bes/5-FU及其代谢产物5-FU在大鼠体内的血药浓度;Bes/5-FU在大鼠体内迅速代谢为5-FU。     

5—氟尿嘧啶协同给药途径的药代动力学研究和临床应用

目的：研究５－氟尿嘧啶（５－Ｆｕ）腹腔、静脉和灌胃３种给药途径化疗的优劣。方法：采用高效液相色谱不比较研究了家兔５－Ｆｕ３种给药途径的药代动力学。结果：大剂量航空给药能在腹腔,门静脉及肝脏提供高浓度药物,且维持时间较长。静脉给药周围血药浓度及门静脉血药浓度均较高,但有效血药浓度维持时间短,灌胃给药后,腹腔液药浓度极低,门静脉血药浓度虽然高于周围血,但吸收极不规则,个体差异较大。组织中药物浓度测定发     

苯妥英钠药代动力学实验的临床意义

目的 对苯妥英钠进行药物动力学研究,制定苯妥英钠个体化给药方案.方法 一次性口服给药,多点采样,分光光度法测定血药浓度,绘制时间-血药浓度曲线,用剩余法原理计算动力学参数.结论 根据该患者药代动力学参数,准确制定个体化给药方案,调整所预期的血药浓度.结论 单一患者进行苯妥英钠药代动力学研究,对制定个体化给药方案更具有临床意义.     

儿童地高辛血药浓度监测分析

地高辛属于强心甙类药,是一类选择性地作用于心脏、增加心肌收缩力的药物.其具有正性肌力、负性频率、负性传导作用.由于地高辛安全范围窄,药物动力学和药效学个体差异大等原因,必须在血药浓度监测下合理应用,才能保证给药的安全性和有效性.现报道地高辛血药浓度监测指导儿童心脏病治疗30例,为临床实行个体化给药提供依据.     

二氢嘧啶脱氢酶活性替代值在结直肠癌化疗中个体化给药的应用

目的:在氟尿嘧啶(5-FU) 醛氢叶酸(CF)结直肠癌化疗方案中,测定二氢嘧啶脱氢酶(DPD)活性替代值并评价与5-FU血药浓度及毒性级别的相关性.方法:以高效液相色谱法测定结直肠癌患者体内内源性嘧啶类物质二氢尿嘧啶(UH2)与尿嘧啶(U)的比值,作为DPD活性的替代值,同时行连续5 d的5-FU CF辅助化疗方案,第5天监测5-FU血药浓度,评价DPD酶活性替代值与5-FU血药浓度及毒性的相关性.结果:50例结直肠癌患者行5-FU CF辅助化疗方案,化疗前测定DPD酶活性替代值为(4.2±1.2),5-FU的血药浓度为(2 203.6±612.4)μg·L-1,DPD酶活性替代值与5-FU血药浓度、5-FU毒性级别呈负相关.结论:血中DPD酶活性替代值(UH2/U值)的测定可作为5-FU结直肠癌化疗时的血药浓度及毒性的预测指标,修正5-FU按体表面积的给药方式,为结直肠癌5-FU化疗个体化剂量的确定提供更为可靠的理论依据.     

复方雷尼替丁分散片在Beagle犬体内的时辰药物动力学

目的对Beagle犬早、晚服用复方雷尼替丁分散片后,探讨其血药浓度及药物动力学参数的时辰变化规律,为制定给药方案提供参考。方法采用RP-HPLC法,测定6只Beagle犬于早、晚分别给予复方雷尼替丁分散片后不同时间的血药浓度,将计算得到的药物动力学参数进行统计分析。结果雷尼替丁血药浓度在Beagle犬体内存在明显的节律性,早上给药组的药时曲线下面积(AUC)和达峰浓度(ρmax)均高于晚上给药组(P<0.05),其他药物动力学参数没有显著性差异(P>0.05)。结论雷尼替丁在Beagle犬体内血药浓度随着昼夜更替呈现节律性变化。     

卡马西平治疗儿童癫痫的血药浓度监测与合理用药

目的:研究儿童癫痫患者服用卡马西平后,其血药浓度、给药剂量及给药时间的关系。方法:对服用卡马西平及联合用其他抗癫痫药物的51例癫痫患儿,用荧光偏振免疫法(FPIA)监测其血药浓度,并结合疗效进行统计分析。结果:稳态血药浓度与给药剂量、给药时间、是否联合用药等有着密切的关系。结论:儿童癫痫患者服用卡马西平后的血药浓度个体差异大,及时监测血药浓度、调整给药剂量及给药时间,对控制儿童癫痫发作有重要意义。     

万古霉素血药浓度低于目标治疗浓度因素分析及给药方案优化

摘要：万古霉素是临床用于治疗严重革兰阳性菌感染的一线用药,其药物动力学特性受多因素的影响,药动学参数个体差异较大,在临床应用中常出现血药浓度偏低。为优化万古霉素的临床应用,本文检索文献,总结部分特殊群体中导致万古霉素血药浓度偏低的因素并给出相关剂量调整建议。总的来说,可通过给予个体化的负荷剂量、采取缩短给药间隔或持续输注的后续给药方式、结合贝叶斯法监测AUC等方式来优化万古霉素给药。     

肿瘤患者个体差异对卡培他滨药物代谢动力学影响

目的:研究个体差异(性别、年龄、体表面积及体质量)对肿瘤患者体内卡培他滨的药代动力学的影响,为临床合理使用卡培他滨提供依据。方法:选取76例不同类型肿瘤患者为研究对象,餐后口服卡培他滨片0.6 g(0.15 g,4片)后进行多点采集血样,HPLC-MS/MS检测受试者给药后血浆中的卡培他滨及其活性代谢物5-氟尿嘧啶(5-FU)的血药浓度,Phoenix WinNonlin7.0软件计算卡培他滨和5-FU的药动学参数AUC 0-∞和C max,研究性别、年龄、体表面积及体质量与卡培他滨及5-FU药动学的相关性。结果:男性卡培他滨C max比女性高49%,卡培他滨AUC 0-∞及5-FU的C max和AUC 0-∞值在性别之间没有区别。受试者年龄(26~65岁)与卡培他滨C max负相关(P<0.05),而与卡培他滨AUC 0-∞及5-FU的AUC 0-∞和C max无相关性;不同体表面积(1.28~2.01 m 2)患者卡培他滨的AUC 0-∞和C max值无明显差异,而5-FU的AUC 0-∞和C max随着体表面积的增加而减少。不同体质量(45.0~83.0 kg)患者体内卡培他滨的AUC 0-∞和C max的值无明显差异,但5-FU的AUC 0-∞和C max差异具有统计学意义(P<0.05)。结论:现有研究对象结果显示不同的个体差异因素对于卡培他滨的药动学影响不同。其中,性别和年龄主要影响卡培他滨吸收,而体表面积和体质量是卡培他滨的代谢过程主要影响因素。     

Effect of gastrectomy on the pharmacokinetics of 5-fluorouracil and gimeracil after oral administration of S-1

The effect of gastrectomy on pharmacokinetics after S-1 administration was investigated in a total of 12 cases - nine in which partial gastrectomy was performed and three in which total gastrectomy was performed. A single oral dose of S-1, 50 mg as tegafur, was administered, serial peripheral blood samples were collected, and the concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) were measured. The pre-operative S-1 dose was administered about 7 days before surgery and the post-operative dose was administered around post-operative hospital day 14. In the partial gastrectomy cases the maximum post-operative blood concentration (Cmax) of 5-FU and CDHP tended to be lower than before surgery, and the difference in 5-FU concentrations was significant. The area under the blood concentration-time curve (AUC0-8 h) for CDHP was significantly smaller post- than pre-operatively, but no significant difference was observed with regard to 5-FU. In the total gastrectomy cases the post-operative tmax of both 5-FU and CDHP was shorter than the pre-operative tmax, and no significant differences were observed between the pre- and post-operative AUC0-8 h values. Thus, the results of the present study showed that around post-operative hospital day 14, when total oral feeding had become possible after surgery for gastric cancer, the AUC0-8 h values of 5-FU and CDHP after S-1 administration were almost the same as before surgery and that gastrectomy had hardly any effect on the pharmacokinetics of S-1.     

Effect of 5-fluorouracil on the anticoagulant activity and the pharmacokinetics of warfarin enantiomers in rats.

The interaction between the antineoplastic agent 5-fluorouracil (5-FU) and the oral anticoagulant warfarin enantiomers was investigated in rats. An increase in hypoprothrombinaemic response, assessed by means of percent changes of prothrombin complex activity and clotting factor VII activity, to warfarin, was observed following oral administration of 1.5 mg/kg racemic warfarin to rats during a 8-day intraperitoneal dose regimen of 5-FU (13.3 mg/kg daily). 5-FU had no apparent effect on the baseline blood coagulation, the in vitro rat serum protein binding as well as the absorption and distribution of the S- and R-enantiomers of warfarin in rats. Yet treatment with 5-FU produced a significant decrease in the total serum clearance value of S-warfarin in rats. The decreased total clearance was attributed mainly to a significant decrease in the formation rate of the overall oxidative metabolites of the more potent S-enantiomer of warfarin.     

高效液相色谱法测定直肠癌术中区域化疗血液、盆腔液和组织5-氟尿嘧啶浓度

目的:测定直肠癌术中区域化疗血液、盆腔液和组织5-氟尿嘧啶浓度。方法:20例直肠癌患者术中行区域化疗,注药后2、5、10、20、30、60min采集门静脉血、周围静脉血、盆腔液和癌旁组织,以高效液相色谱法测定5-氟尿嘧啶浓度。结果:各样本注药后2min即出现峰浓度,此后逐渐降低。其中,盆腔液浓度最高,癌旁组织最低,门静脉血药浓度高于周围静脉血。结论:直肠癌术中区域化疗,可使盆腔液、门静脉血和癌旁组织维持高的药物浓度,这对预防直肠癌术后局部和肝脏转移有指导意义。     

Effect of 5-fluorouracil treatment on SN-38 absorption from intestine in rats

5-Fluorouracil (5-FU)-based chemotherapies with irinotecan have been applied for the treatment of cancers, and a common dose-limiting toxicity is neutropenia and diarrhea. In this study, we investigated the effect of 5-FU treatment on expression levels of drug transporters for SN-38 transportation and SN-38 absorption from the intestine following 5-FU treatment. Expression levels of several drug transporters and nuclear receptors in rats after 5-FU treatment were evaluated. SN-38 absorption from the intestine was evaluated by SN-38 concentration levels in serum following SN-38 injection into the intestine of 5-FU treated rats. The levels of renal multidrug resistance protein 2 (Mrp2) on day 4 after treatment (400 mg/kg) showed significant upregulation, 359.2 ± 33.2% (mean ± S.E.) of control. Mrp2 levels in the intestine were downregulated to 26.2 ± 8.4% of control. 5-FU treatment (400 mg/kg) also significantly downregurated expression levels of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) to 41.2 ± 14.7%, 15.7 ± 4.3% of control, respectively. To evaluate SN-38 absorption from the intestine, SN-38 was loaded in to the intestine on day 4 after 5-FU treatment. Pretreatment with 5-FU significantly increased SN-38 concentration in the blood 30, 60 and 90 min after SN-38 administration. The area under the curve for SN-38 in the 5-FU group was significantly higher than in vehicle groups. 5-FU treatment decreased expression levels of P-glycoprotein and Bcrp in intestine. The present study suggests that combination chemotherapy of 5-FU with irinotecan (CPT-11) may elevate SN-38 absorption from intestine.     

阿托氟啶在肿瘤患者体内的药代动力学研究

目的：通过对肿瘤患者服用阿托氟啶后的械代动力学研究,探讨氟啶在人体内的药代动力学特征。方法：18例恶性肿瘤者随机分成3组,分别po阿托氟啶800,1000和1200mg,采用高效液相色谱法测定用药后不同时间血清中阿托氟啶代谢产物的浓度,并对所测得的血药浓度－时间数据进行拟合,计算药代动力学参数。结果：陈托氟啶在人体内的代谢物为3－邻甲基苯甲酰基－5－氟尿嘧啶（TFU）,后者在体内的代谢符合一房室模型的特征,不同患者对阿托氟啶的代谢存在较大的个体差异。高中低剂量组的阿托氟啶的药代动力学参数没有显著性差异。结论：陈托氟啶的体内代谢存在极大的个体差异,有必要进行治疗药物监测,实现临床用药个体化。     

干扰hENT_1表达增加5-FU在胰腺癌SW1990细胞内浓度

目的明确hENT1在5-FU跨膜转运和返流中的作用,以及返流对5-FU在细胞内浓度的影响。方法将能特异性下调hENT1的重组及对照质粒用脂质体法转染到SW1990细胞内,RT-PCR检测hENT1 mRNA表达情况。分别培养SW1990、pSilence-hENT1Si SW1990、pSilence-Control SW1990细胞,3组细胞均置于含5-FU100mg·L-1的DMEM中温浴。各组取等量细胞刮取液两份,一份用毛细管区带电泳测定5-FU含量、另一份作平行样本测定蛋白含量,最后计算细胞内5-FU浓度。结果pSilence-hENT1Si SW1990细胞hENT1 mRNA表达水平下调0.5。SW1990组用5-FU温浴后,细胞内5-FU浓度在早期迅速升高,120min后处于平台期。pSilence-hENT1Control-SW1990组与SW1990组相比无差异(P>0.05)。而pSilence-hENT1SiSW1990细胞内5-FU浓度早期上升较慢,但随着时间延长,浓度逐渐升高,120min后细胞内浓度稳定,高于对照组中浓度(P<0.05)。结论干扰hENT1表达可以提高5-FU在SW1990细胞内浓度。hENT1是SW1990细胞向外返流5-FU的主要通道。     

64例老年患者万古霉素血药浓度监测结果分析

目的:通过分析64例老年肺部感染患者万古霉素血药浓度的监测结果,为临床合理用药提供参考.方法:采用荧光偏振免疫法测定万古霉素的血药浓度,对64例157例次血药浓度监测结果进行比较分析.结果:患者万古霉素血清峰浓度和谷浓度均在治疗窗范围内的仅占40% 左右,而谷浓度高于正常范围及峰浓度低于正常范围的约占50% ;首剂饱和方案组与首剂未饱和方案组中血清峰浓度比较有显著性差异,而谷浓度无显著性差异;肾功能正常组患者用药前、后内生肌酐清除率有显著性差异,尿素氮无显著性差异,而肾功能损害组患者用药前、后尿素氮及内生肌酐清除率均无显著性差异;近45% 的患者给药方案为500 mg,每日2~3 次,约75% 的患者未能达到有效峰浓度,约60% 的患者谷浓度超过正常水平.结论:老年感染患者使用万古霉素个体差异很大且多数患者伴有肾功能轻中度损害,应尽量给予首剂饱和方案并对其进行血药浓度监测,以利于实现个体化给药,进而提高该药应用的有效性和安全性.     

Investigation of 5-FU disposition after oral administration of capecitabine, a triple-prodrug of 5-FU, using a physiologically based pharmacokinetic model in a human cancer xenograft model: comparison of the simulated 5-FU exposures in the tumour tissue between human and xenograft model.

The nonlinear pharmacokinetics of capecitabine, a triple prodrug of 5-FU preferentially activated in tumour tissues, was investigated in human cancer xenograft models. A physiologically based pharmacokinetic (PBPK) model integrating the activation process of capecitabine to 5-FU and 5-FU elimination was constructed to describe the concentration/time profiles of capecitabine and its three metabolites, including 5-FU, in blood and organs. All the biochemical parameters (enzyme kinetic parameters, plasma protein binding and tissue binding of capecitabine and its metabolites) integrated in this model were measured in vitro. The simulated curves for the blood and tumour concentrations of capecitabine and its metabolites can basically describe the observed values. A simple prodrug of 5-FU, doxifluridine, is known to be activated to 5-FU to some extent in the gastrointestinal (GI) tract, causing diarrhoea, which is the dose limiting side effect of doxifluridine. Consequently, the therapeutic index (the ratio of 5-FU AUC in the tumour to that in GI) after the administration of effective dose capecitabine was predicted by this PBPK model and found to be five times and 3000 times greater than that of doxifluridine and 5-FU, respectively. This was compatible with the previous result for the difference in the ratio of the toxic dose to the minimum effective dose between capecitabine and doxifluridine, suggesting that 5-FU preferentially accumulates in tumour tissue after oral administration of capecitabine compared with the other drugs (doxifluridine and 5-FU). The 5-FU AUC in tumour tissue of human cancer xenograft models at the minimum effective dose was comparable with those estimated for humans at the clinical dose. In addition, the predicted therapeutic indices at the respective doses were correlated well between humans and mice (xenograft model). These results suggest that the 5-FU AUC in human tumour tissue at its clinically effective dose can be predicted based on the PBPK model inasmuch as the 5-FU AUC in a human cancer xenograft model at its effective dose may be measured or simulated.     

Enhanced liver targeting of 5-fluorouracil using galactosylated human serum albumin as a carrier molecule

The objective of this study was to develop a liver-specific antihepatocarcinoma agent. The galactosylated human serum albumin 5-fluorouracil conjugate (GHSA-5-FU) was prepared and tested for its chemical characteristic, biodistribution and primary cytotoxicity. The matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was applied to determined the molar ratio (moles of 5-FU/mole of G-HSA and moles of galactose/mole of HSA) of the conjugate. The liver targeting ability of GHSA-5-FU labeled by (131)I was evaluated by measuring the total radioactivity in organs after i.v. administration in mice and rabbits, and the cytotoxicity of the conjugate was assayed by MTT method. The results showed that the molar ratio of galactose to HSA was 50, and the 5-FU to GHSA was 15. Liver uptake in rabbits and mice peaked within 5-20 min after injection. The radioactivity (counts/g tissue) of the conjugate in the liver was several times higher than those in the other organs. The conjugate showed strong cytotoxicity, but no significant cytotoxicity difference was found between GHSA-5-FU and free 5-FU.